The present invention is related to a novel hexacyclic compound of formula [1], 
wherein
Z, R3 and R4 are as defined below. These compounds have antitumor activities and are useful in the treatment of cancer. The invention also relates to pharmaceutical compositions containing an amount of a compound of formula [1], as well as to a method of treating cancer comprising administering a therapeutically effective amount of a compound of formula [1].
4(S)-ethyl-4-hydroxy-1H-pyrano[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione (camptothecin), a pentacyclic alkaloid isolated from the Chinese tree Camptotheca acuminata, was first discovered in 1960""s by Wall et al. as an anti-tumor agent (Wall, M. E. et al. Plant tumor antigens. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibition from Camptotheca acuminata. J. Am. Chem. Sco., 88:3888-3890, 1966). Cytotoxic activity of camptothecin is attributable to its ability to interfere with DNA topoisomerase I (Hsiang, Y.-H. et al. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem., 260:14873-14878, 1985). DNA topoisomerase I is a phosphorylated protein and is required for DNA replication, transcription and recombination. It forms a covalent reversible DNA topoisomerase I-double strand DNA complex (referred to as cleavable complex) and relaxes supercoiled DNA by cleaving and religating one of the two DNA strands (Wang, J. C. DNA topoisomerases. Annu. Rev. Biochem. 54:665-697, 1985; Champoux, J. J. Mechanistic aspects of type-I topoisomerase. In xe2x80x9cDNA topology and its biological effectsxe2x80x9d pp. 217-242, 1990; Wang, J. C. et al. The role of DNA topoisomerase in recombination and genome stability: A double-edged sword? Cell 62:403-406, 1990; Muller, M. T. Quantification of eukaryotic topoisomerase reactivity with DNA. Preferential cleavage of supercoiled DNA. Biochim. Biophys. Acta. 824:263-267, 1985). Camptothecin reversibly interacts with the cleavable complex and subsequently induces DNA single strand breaks by interfering with the religation step (Hsiang, Y.-H. et al. Camptothecin induces protein-linked DNA DNA brasks via mammalian DNA topoisomerase I. J. Biol. Chem., 260:14873-14878, 1985; Porter, S. E. et al. The basis for camptothecin enhancement of DNA breakage by eukaryotic DNA topoisomerase I. Nucleic Acid Res. 17:8521-8532, 1989). Unlike DNA topoisomerase II, DNA topoisomerase I-mediated relaxation of DNA occurs independently of nucleotide cofactor, or divalent cations.
Although DNA topoisomerase I is an ubiquitous enzyme and is present throughout the cell cycle, antiproliferative activities of camptothecin are only limited to clinical trials, and half-life in plasma of camptothecin appeared to be short (less than 30 min) being converted to the inactive carboxylate form. Furthermore, campthotecin is poorly soluble in water, and therefore, it itself can not be formulated for the use of intravenous injection. A number of camptothecin derivatives were synthesized to improve anti-tumor activity, lactone stability in plasma and/or water solubility, and were tested clinically (Gerrits, C. J. H., de Jonge, M. J. et al. Topoisomerase I inhibitors: the relevance of prolonged exposure for clinical development. Br. J. Cancer, 76: 952-962, 1997; O""Leary, J. et al. Camptothecins: a review of their development and schedules of administration. Eur. J. Cancer, 34: 1500-1508, 1988; Gerderblom, H. A. et al. Oral topoisomerase I inhibitors in adults patients: present and future. Investig. New Drugs, 17: 401-415, 1999). However, at the present time, only two campthotecin derivatives, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (irinotecan) that is the prodrug of 7-ethyl-10-hydroxycamptothecin (SN-38, EP 0074256) and 9-(dimethylamino)methyl-10-hydroxycamptothecin (topotecan) have been introduced to for the clinical practice (Kunimoto, T. et al. Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res., 47:5944-5947, 1987; Kingsbury, W. D. et al. Synthesis of water-soluble (aminoalkyl)camptothecin analogs: inhibition of topoisomerase I and antitumor activity. J. Med. Chem., 34:98-107, 1991).
Due to its complexities of the synthetic routes, there is clearly a limitation for producing camptothecin. As was the case of irinotecan or topotecan, large majority of the camptothecin analogues were the camptothecin derivatives having substituents on the A-ring or B-ring independently. Such camptothecin derivatives include 9-nitrocamptothecin (Pantazis, P. et al. The role of pH and serum albmin in the metabolic conversion of 9-nitrocamptothecin to 9-aminocamptothecin by human hematopoietic and other cells. Eur. J. Hematol., 55:211-213, 1995; Loos, W. J. et al. Determination of the lactone and lactone plus carboxylate forms of 9-aminocamptothecin in human plasma by sensitive high-performance liquid chromatography with fluorescent detection. J. Chromatogr. B., 694: 435-441, 1997; Blaney, S. M. et al. Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan, and SN-38 in nonhuman primates. Cancer Chemother. Pharmacol., 41: 464-468, 1998), and lurtotecan (Emerson, D. L. et al. In vitro anti-tumor activity of two new seven-substituted water-soluble camptothecin analogues. Cancer Res., 55:603-609, 1955).
Few derivatives, such as (1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3xe2x80x2,4xe2x80x2:6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione methanesulfonate (DX-8951f), having the F-ring over the A- and B-ring were also reported to possess potent anti-tumor activities both in vitro and in vivo(Vey, N. et al. The topoisomerase I inhibitor DX-8951f is active in a severe combined immunodeficient mouse model of human acute myelogenous leukemia. Clin. Cancer Res., 6:731-736, 2000). However, the F-ring introduced to the particular position is restricted to a saturated hydrocarbon chain with or without a heteroatom involved in the chain due to the limitations of their synthetic routes.
Based on the deficiencies of the prior art, there are still strong needs to discover new synthetic routes and deliver of new camptothecin analogs with improved activities against wide variety of tumor cells.
In accordance with the present invention it has found that the novel hexacyclic compounds show antitumor activity. The present invention is directed to these novel hexacyclic compounds having potent anti-tumor activity, a process for producing the same, pharmaceutical compositions containing said compounds and processes for producing the novel hexacyclic compounds.
It is an aspect of the present invention to provide hexacyclic compounds of the formula [1], 
wherein
Z is xe2x80x94NHxe2x80x94C(xe2x95x90X)xe2x80x94N(R1)xe2x80x94 or xe2x80x94Nxe2x95x90C(R2)xe2x80x94N(R1)xe2x80x94;
R1 is hydrogen; (C1-C10) alkyl, optionally substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(C1-C5) alkylamino, di-(C1-C5) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
R2 is hydrogen; amino; (C1-C5) alkyl; (C1-C5) alkoxy; (C1-C5) alkylthio; mono-(C1-C5) alkylamino; di-(C1-C5) alkylamino optionally substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, (C3-C7) cycloalkyl, heterocyclic ring or an aryl ring in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
R3 and R4 are independently hydrogen, halogen or (C1-C5) alkyl; and
X is oxygen or sulfur;
or a pharmaceutically acceptable salt thereof.
A more specific aspect of the present invention is provide hexacyclic compounds of the formula [1A], 
wherein X is oxygen and R1 is hydrogen; (C1-C10) alkyl, optionally substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(C1-C5) alkylamino, di-(C1-C5) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino; and
R3 and R4 are independently hydrogen, halogen or (C1-C5) alkyl; or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention to provide hexacyclic compounds of the formula [1B], 
wherein R1 is hydrogen; (C1-C10) alkyl, optionally substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, mono-(C1-C5) alkylamino, di-(C1-C5) alkylamino, (C3-C7) cycloalkyl, a heterocyclic ring and an aryl ring in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C1-C5) alkylamino and di-(C1-C5) alkylamino;
R2 is hydrogen; amino; (C1-C5) alkyl; (C1-C5) alkoxy; (C1-C5) alkylthio; mono-(C1-C5) alkylamino; di-(C1-C5) alkylamino optionally substituted with one to three moieties independently selected from the group consisting of (C1-C5) alkoxy, hydroxy, halogen, amino, (C3-C7) cycloalkyl, heterocyclic ring and an aryl ring in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5) alkylamino or di-(C1-C5) alkylamino;
R3 and R4 are independently hydrogen, halogen or (C1-C5) alkyl; and
or a pharmaceutically acceptable salt thereof.
It is yet another aspect of the present invention to provide pharmaceutical composition containing the above compounds.
A still further aspect of the present invention is to provide a process for the preparation of the above hexacyclic compounds.